Oxazolidinones are prominent among the new Gram-positive antimicrobial agents now becoming available. Oxazolidinones bind to the 50S subunit of the prokaryotic ribosome, preventing formation of the initiation complex for protein synthesis. This is a novel mode of action. Other protein synthesis inhibitors either block polypeptide extension or cause misreading of mRNA. Linezolid (N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide) is the first approved antimicrobial oxazolidinone for clinical use in the United States and elsewhere.
Linezolid minimal inhibitory concentrations (MICs) vary slightly with the test mode, laboratory, and significance attributed to thin hazes of bacterial survival, but all workers find that the susceptibility distributions are narrow and unimodal with MIC values between 0.5 and 4 μg/mL for streptococci, enterococci and staphylococci. Full activity is retained against Gram-positive cocci resistant to other antibiotics, including methicillin-resistant staphylococci and vancomycin-resistant enterococci. MICs are 2-8 μg/mL for Moxorella, Pasteurella and Bacteroides spp. but other Gram-negative bacteria are resistant as a result of endogenous efflux activity as well as the intake presented by Gram-negative bacteria outer membrane cell.
Linezolid is indicated for the treatment of adult patients with the following infections:    nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains) or Streptococcus pneumoniae (including multidrug-resistant strains [MDRSP]). MDRSP refers to isolates resistant to two or more of the following antibiotics: penicillins, second-generation cephalosporins, macrolides, tetracyclines, and trimethoprim/sulfamethoxazole;    complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae;     uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible only) or Streptococcus pyogenes;     vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia; and    community-acquired pneumonia caused by Streptococcus pneumoniae (including multidrug-resistant strains [MDRSP]), also in cases with concurrent bacteremia, or caused by Staphylococcus aureus (methicillin-susceptible strains only).
Oxazolidinones were originally developed as MAO inhibitors for treatment of depression and Parkinson's disease. MAO is one of the primary enzymes responsible for the catabolism of catecholamines. In humans, MAO occurs in two isoforms, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin (5-HT) and norepinephrine; MAO-B preferentially deaminates phenylethylamine, benzylamine, and, in man, dopamine. Normally MAO-A inhibitors, such as moclobemide or tranylcypromine, have been used as antidepressant agents while MAO-B inhibitors, such as selegiline, have been used preferably in the therapy of Parkinson's disease. U.S. Pat. No. 3,655,687 discloses 5-hydroxymethyl-3-substituted-2-oxazolidinone derivatives with significant antidepressant activity. A compound disclosed in this patent, toloxatone, 5-(hydroxymethyl)-3-(3-methylphenyl)-2-oxazoidinone, is of particular reference.
Toloxatone is a selective, reversible inhibitor of MAO-A and has been introduced in clinical practice. Because of this reason, particular attention has been paid to the question of whether evidence of adverse interaction with drugs known to be metabolized by monoamine oxidase would occur in patients treated with linezolid. An enhanced pressor response has been seen in patients taking certain adrenergic agents, including phenylpropanolamine and pseudoephedrine, and it is specifically noted that the doses of these drugs should be reduced in patients receiving linezolid. Animal studies suggest that linezolid moderately potentiates the pressor effects of the endogenous and dietary amine, tyramine, and other sympathomimetic amines. The package insert for linezolid warns against combining it with tyramine-rich foods and about being aware of a potential interaction with adrenergic and serotonergic agents. Accordingly, there is a need of new oxazolidinone antimicrobial compounds with minimum MAO inhibitory activity to eliminate the related side effects from potential drug-drug interactions.
The preparation of linezolid is disclosed in PCT application WO 9507271.
PCT application WO 03084534 discloses a method for treating a diabetic foot infection with oxazolidinones, specially with 3-{4-[1-(2,3-dihydroxy-propionyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3,5-difluoro-phenyl}-5-(isoxazol-3-ytoxymethyl)-oxazolidin-2-one; 2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(4-glycoloyl-piperazin-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide; and linezolid.
PCT application WO 03063862 discloses a method of treating a patient in need of oxazolidinone by administering an effective amount of oxazolidinone and an effective amount of at least one vitamin selected from the group consisting of vitamin B2, vitamin B6, vitamin B12 and folic acid. Patent applications DE 10105989 and US 2003/0153610 disclose the preparation of the N-((2-oxo-3-phenyl-1,3-oxazolidin-5-yl)-methyl)-heterocyclic amides and their use for inhibiting blood coagulation in vitro, especially in preserved blood or biological samples containing factor Xa. Heterocyclic amides disclosed in US 2003/0153610 are limited to thienyl amides, while DE 10105989 focuses on N-[[3-[(4-substituted)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-amides with substituents containing either the oxo- or N-oxide moiety. Moreover, these documents describe neither antibacterial nor MAO inhibitory activity.
WO 04007489 describes some oxazolidinone derivatives having antibacterial activity against Gram-positive and Gram-negative bacteria. In this patent application some of the limitations which appeared during the clinical development and use of linezolid and its potential congeners were pointed out: It is said that this class of compounds has a propensity to induce myelosuppresion with consequent thrombocytopenia and that the inhibition of monoamine oxidase by oxazolidinones has prompted clinicians to recommend the use of members of this class with caution during concomitant usage of adrenergic or serotonergic agents and selective serotonin reuptake inhibitors.
WO 04089944 describes certain substituted phenyl oxazolidinones which are useful antimicrobial agents against a number of human and veterinary pathogens, including gram positive aerobic bacteria as well as anaerobic organisms. In this document, no mention is made about the inhibitory activity of the monoamine oxidase.
Thus, it is apparent that, despite all the research efforts made in the past, there is still a need to find new effective antibacterial agents, having low side effects than those known in the art.